Best Practice & Research Clinical Obstetrics and Gynaecology 34 (2016) 66e73

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Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn

Infertility and uterine fibroids

Leonidas I. Zepiridis, MD, PhD, Assistant Professor,

Grigoris F. Grimbizis, MD, PhD, Professor,
Basil C. Tarlatzis, MD, PhD, Professor *
First Department of Obstetrics and Gynaecology, Papageorgiou University Hospital, Aristotle University of
Thessaloniki, Greece

Uterine fibroids are the most common tumors in women and their
Keywords:
prevalence is higher in patients with infertility. At present, they are
uterine fibroid
myoma classified according to their anatomical location, as no classification
infertility system includes additional parameters such as their size or number.
fertility There is a general agreement that submucosal fibroids negatively
affect fertility, when compared to women without fibroids. Intra-
mural fibroids above a certain size (>4 cm), even without cavity
distortion, may also negatively influence fertility. However, the
presence of subserosal myomas has little or no effect on fertility.
Many possible theories have been proposed to explain how fi-
broids impair fertility: mechanisms involving alteration of local
anatomical location, others involving functional changes of the
myometrium and endometrium, and finally endocrine and para-
crine molecular mechanisms. Nevertheless, any of the above
mentioned mechanisms can cause reduced reproductive potential,
thereby leading to impaired gamete transport, reduced ability for
embryo implantation, and creation of a hostile environment.
The published experience defines the best practice strategy, as not
many large, well-designed, and properly powered studies are
available. Myomectomy appears to have an effect in fertility
improvement in certain cases. Excision of submucosal myomas
seems to restore fertility with pregnancy rates after surgery similar
to normal controls. Removal of intramural myomas affecting
pregnancy outcome seems to be associated with higher pregnancy
rates when compared to non-operated controls, although evidence
is still nοt sufficient. Treatment of subserosal myomas of

* Corresponding author. First Department of Obstetrics and Gynaecology, Papageorgiou Hospital, Medical School of Aristotle
University of Thessaloniki, Greece.
E-mail address: basil.tarlatzis@gmail.com (B.C. Tarlatzis).

http://dx.doi.org/10.1016/j.bpobgyn.2015.12.001
1521-6934/© 2015 Elsevier Ltd. All rights reserved.
 L.I. Zepiridis et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 34 (2016) 66e73 67

reasonable size is not necessary for fertility reasons. The results of

endoscopic and open myomectomy are similar; thus, endoscopic
treatment is the recommended approach due to its advantages in
patient's postoperative course.
© 2015 Elsevier Ltd. All rights reserved.

General issues

Uterine fibroids are the most common tumors in women and are almost always benign [1].
Moreover, they are highly dependent on the ovarian steroids. Although their cellular origin remains
unknown, they are considered to be monoclonal tumors, arising from the mutation of a single myo-
metrial somatic stem cell after multiple cycles of growth followed by involution under hormonal in-
fluence [1].
According to recently published data, approximately 7e8 out of 10 women will have a fibroid during
their lifetime [1]. Pathological examination of hysterectomy specimens also revealed prevalence of
>75% [2]. Nevertheless, their overall rate does not seem to exceed 8e10% in 30e40 years [1].
It is worth noting that the prevalence of fibroids is higher in patients with infertility [3]. Thus,
among women undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), more
than one out of four women do have fibroid(s), although it is estimated that if all other causes of
infertility are excluded, fibroids might be responsible for only 2e3% of the cases [1]. Therefore, fibroids
are the most common benign uterine condition, and their location and size determine their clinical
presentation, if any.

Classification

Fibroids represent a heterogeneous disease, varying from a single small lesion to multiple extra
large lesions that may fill the whole peritoneal cavity [1,4] having different location characteristics.
Similarly, the reproductive prognosis and clinical presentation of women with fibroids are variable,
from totally asymptomatic to symptomatic requiring treatment.
There is no widely accepted classification system to categorize fibroids. Fibroids are generally
classified according to their anatomical relationship with the myometrium and endometrium. Thus, at
present, the fibroid location is the only basic criterion for classification, while additional parameters
such as the size or the number are not taken into account, although they could have a prognostic role
for their clinical significance. Thus, any correlation effort makes the assessment and any comparisons
difficult [2].
Usually, they are divided into three topographic categories: the submucosal, the intramural, and the
subserosal fibroids. According to the needs of hysteroscopic treatment, the submucosal category is

Table 1
Fibroid classifications systems.

Fibroid Classification
Classical FIGO (2011)

Submucosal e type 0 100% intracavity 0

Submucosal e type I >50% intracavity 1
Submucosal e type II <50% intracavity 2
Intramural In contact with endometrium 3
Intramural 100% intramural 4
Intramural Intramural but <50% subserosal 5
Subserosal Subserosal but <50% intramural 6
Subserosal Pedunculated 7
68 L.I. Zepiridis et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 34 (2016) 66e73

further divided into type 0 (the fibroid is inside the endometrial cavity), type I (>50% of the fibroid
protrudes into the endometrial cavity), and type II myomas (<50% of the fibroid protrudes into the
endometrial cavity) (Table 1).
Aiming to provide a more universal and detailed classification, Federation of Gynecology and Ob-
stetrics (FIGO) proposed the classification of fibroids into seven types, that is, from type 0, where the
subserosal part is totally inside the uterine cavity, to type 7, where the pedunculated fibroid is inside
the pelvis (Table 1) [5]. This new classification represents an extension of the submucosal subclassi-
fication, including subcategories for the intramural and subserosal fibroids, also depending on the
extent of their occupancy of the muscle and serosa layer of the uterus [5]. However, the prognostic role
as well as the utility of this new system of classification requires further investigation.

Do fibroids affect reproductive potential?

An important question is what is the level of evidence and the significance of the available data to
determine the impact of fibroids on fertility.
In 2007, Somigliana et al. [6] performed a meta-analysis, the first serious attempt in this direction,
studying the effect of fibroids on the reproductive outcome of women. They observed that childbearing
was associated with decreased likelihood of fibroid existence [6]. However, the explanation for this
observation was not clear: fibroids negatively affect fertility or pregnancy “per se” protects against the
development of fibroids. Therefore, meta-analysis of 13 studies including assisted reproduction pa-
tients showed a statistically significant negative effect on clinical pregnancy rates mainly of submu-
cosal (common odds ratio (OR) ¼ 0.3; 95% confidence interval (CI): 0.1e0.7) and to a lesser extent of
intramural fibroids (common OR ¼ 0.8; 95% CI: 0.6e0.9). A similar effect of those two types of fibroids
was also observed on delivery rates. Conversely, the impact of subserosal myomas was not significant
(common OR ¼ 1, 95% CI: 0.7e1.5), and, consequently, these lesions did not seem to play a significant
role in this aspect [6].
Nevertheless, in the same study, the authors concluded that the design of a clear strategy and
formulation of guidelines for the management of subfertile women with fibroids seems to be very
difficult due to the lack of large randomized controlled trials (RCTs). Moreover, they suggested that
physicians should explain to the patients the possible complications of fibroids or myomectomy during
pregnancy, taking into account their age, as well as the number, size, and location of fibroids. Notably,
after 2006, the practice committee of the American Society of Reproductive Medicine (ASRM) has
already adopted this suggestion.
Two years later, in 2009, Pritts et al. [7] attempted answer the same questions through their
meta-analysis. Based on data from 18 studies, they found that the presence of fibroids in general,
regardless of localization, led to a statistically significant decrease in fertility, regarding clinical
pregnancy (risk ratio (RR) ¼ 0.85; 95% CI: 0.73e0.98) and birth rates (RR ¼ 0.69; 95% CI: 0.59e0.82)
and, simultaneously an increase in miscarriage rates (RR ¼ 1.68; 95%CI: 1.37e2.05) [7]. They also
showed that the greatest negative statistical correlation was observed with the submucosal fibroids,
thereby reducing the clinical pregnancy rates up to 70% (RR ¼ 0.36; 95% CI: 0.18e0.74) [7]. Inter-
estingly, even fibroids not interfering with the intrauterine cavity architecture resulted in signifi-
cantly lower birth rates (RR ¼ 0.78; 95% CI: 0.69e0.88) and higher miscarriage rates (RR ¼ 1.89; 95%
CI: 1.47e2.43) [7].
When all studies were included in the meta-analysis, they further observed that the intramural
fibroids had the same effects on clinical pregnancy, (RR ¼ 0.81; 95%CI: 0.70e0.94), live birth
(RR ¼ 0.70; 95% CI: 0.58e0.85), and miscarriage rates (RR ¼ 1.75; 95% CI: 1.23e2.49). Narrowing the
analysis to only prospective studies, although they failed to find a significant decrease in clinical
pregnancy rates, they still observed impaired implantation (RR ¼ 0.55; 95% CI: 0.39e0.78) and live
birth rates (RR ¼ 0.46; 95% CI: 0.29e0.74) as well as higher abortion rates (RR ¼ 2.38; 95% CI:
1.11e5.12) [7].
Based on these findings, the authors concluded that both patients with fibroids affecting the
endometrial cavity and those with fibroids located in the muscular layer, even not affecting the
endometrial cavity architecture, have poorer reproductive outcomes compared to patients without
fibroids. However, subserosal fibroids do not seem to generate any obvious fertility issue [7].
 L.I. Zepiridis et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 34 (2016) 66e73 69

In 2010, Sunkara et al. [8] published another meta-analysis on this subject, focusing only on the
“gray” zone fibroids. It was almost unanimously accepted that the submucosal fibroids are mostly
detrimental to fertility, while the subserosal ones do not harm or interfere with fertility, when of
reasonable sizes.
However, with regard to intramural fibroids, the authors meta-analyzed 19 trials including 6089
patients, of which five were prospective studies with 1127 patients; these patients had intramural
fibroids of size ranging, between 0.7 and 5 cm, which do not interfere with the intrauterine cavity. The
authors tried to investigate if the existence of fibroid affected the outcomes of IVF [8]. When all studies
were taken into account, they found that in women undergoing IVF, the fibroids not reaching the
endometrium and not disrupting the endometrial cavity at all are associated with significantly lower
clinical pregnancy (RR ¼ 0.85; 95% CI: 0.77e0.94) and live birth rates (RR ¼ 0.79; 95% CI: 0.70e0.88)
[8]. However, when they included the five prospective studies, then a significant decrease in live birth
rates was observed (RR ¼ 0.6; 95% CI: 0.41e0.87) [8]. Thus, they concluded that the presence of non-
cavity-distorting intramural fibroids was associated with adverse pregnancy outcomes by reducing
expected live birth rates, although they acknowledged that well-designed RCTs were necessary to
address this question [8].
Although intramural location of fibroids seems to interfere with fertility potential, additional pa-
rameters such as the size and number could also play a critical role. Somigliana et al. [9] compared
patients with asymptomatic intramural or subserosal fibroids of size <5 cm with controls and found
similar live birth rates in both groups, thereby concluding that the presence of asymptomatic small
fibroids did not affect assisted reproductive technique (ART) outcomes [9]. By contrast, Oliveira et al.
[10] found that patients with intramural fibroids of size >4 cm had statistically lower pregnancy rates
than those with intramural fibroids of size <4 cm [10]. Furthermore, in a recent study, Yan et al. [11]
reported that patients with intramural fibroids with the largest diameter (>2.85 cm) had signifi-
cantly lower delivery rates when compared with matched controls without fibroids (adjusted
OR ¼ 0.86; 95% CI: 0.74e0.99) [11]. It seems, therefore, that size is probably a critical independent
variable for the intramural fibroids not affecting the architecture of endometrial cavity. Apparently, the
fibroids could play a significant role in the fertility potential of the woman only if their size was
>3e4 cm [11].

Mechanisms of action

As mentioned above, fibroids have adverse effects on reproduction, as they are associated not only
with infertility and early pregnancy complications but also with adverse obstetric outcomes [2].
Several possible theories have been proposed in order to explain how fibroids may impair fertility:

a) Mechanisms involving alteration of local anatomy, which is associated with the anatomic
distortion of the endometrial cavity or the obstruction of the fallopian tubes. Histological ob-
servations include elongation and distortion of the glands, cystic glandular hyperplasia, polyp-
osis, and endometrial venule ectasia, which may play a significant role [6].
b) Mechanisms involving functional changes, for example, increased uterine contractility, impair-
ment of the endometrial blood supply, and chronic endometrial inflammation. One of the most
frequently observed histological changes attributed to fibroids is glandular atrophy and ulcer-
ation, affecting the proximal and even the distal part of the endometrium [6].
c) Endocrine mechanisms supported by the theory of an abnormal local hormonal milieu
[1,3,7,2,4].
d) Finally, fibroids may induce paracrine molecular effects on the adjacent endometrium, for
example, secretion of vasoactive amines and local inflammatory substances to the extent that
they are capable of impairing fertility [12].

It is also possible that more than one of these mechanisms may be present simultaneously,
contributing in varying degrees, to fertility impairment. Nevertheless, any of the above mechanisms
may lead to impaired gamete transport and reduced ability for embryo implantation [2], possibly
70 L.I. Zepiridis et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 34 (2016) 66e73

through the creation of a hostile environment for gametes or the zygote, thereby leading to reduced
reproductive potential. It is also important to consider that the location of fibroids is the main
parameter affecting fertility outcome.

Does myomectomy restore reproductive potential?

It is quite reasonable to assume that if all these reported results are true, excising the causa causans
(the fibroids in this case), the infertility issue would be resolved, thus restoring fertility of the patient
after the intervention. However, surgical excision of myomas is always associated with myometrial
trauma, repaired by suturing and scar healing, with potential functional consequences due to defective
myometrium and adhesion formation. Treatment of submucosal myomas with hysteroscopic myo-
mectomy results in trauma to the endometrial cavity, with the same potential implications. Thus, the
issue of the surgical treatment of myomas is not simple, involving a highly demanding clinical dilemma
for gynecologists and fertility specialists: will fertility return to the patient after fibroid excision?
Somigliana et al. [6], in their comprehensive review, examined the success rate after abdominal
myomectomy. The postsurgical pregnancy rate in the prospective studies was 57% (95% CI: 48e65) [6].
When focusing on women with otherwise unexplained infertility, this rate was 61% (95% CI: 51e70) [6].
In a review of prospective and retrospective studies, Donnez and Jadoul [13] found a pooled pregnancy
rate of 45% (95% CI: 40e50) in patients who underwent hysteroscopy and 49% (95% CI: 46e52) in those
with laparoscopic/abdominal myomectomy [13]. These post-myomectomy pregnancy rates were
further confirmed by more recent, large studies [4]. However, the lack of randomized control trials
represents a serious limitation to the assessment of the effect of myomectomy on woman's fertility [6].
Despite the large number of series reporting the pregnancy rates after myomectomy, comparative
studies are scarce and randomized control trials extremely rare. Bulletti et al. [14] investigated the role
of myomectomy in a study of 106 patients with fibroids who underwent laparoscopic removal
compared to 106 patients who did not and 106 patients with unexplained infertility without myomas.
Patients were followed up for 9 months after allocation. Delivery rates were significantly higher in the
group of laparoscopically treated patients (42%) than in the group of non-treated patients with fibroids
(11%, p < 0.001) and patients without myomas (25%, p < 0.001) [14]. The same authors [15], 5 years
later, compared myomectomy results to expectant management prior to IVF. Patients with at least one
intramuralesubserosal fibroid of size >5 cm were informed about the advantages and drawbacks of
myomectomy and were then divided into two groups with similar characteristics (myomectomy and
expectant management) upon their own decision [15]. The cumulative delivery rate in women who did
and did not undergo surgery was 25 and 12%, respectively (p < 0.01) [15]. Despite the fact that those
two studies were not randomized [6], they provide evidence for the beneficial role of myomectomy in
the fertility potential of the women. Casini et al. [16] performed a prospective randomized control trial
examining the pregnancy rates in women with fibroids who underwent laparoscopic and/or hyster-
oscopic myomectomy, compared to those who did not. They found significantly higher pregnancy rates
in women with submucous myomas who were treated surgically than those who did not (43.3% vs.
27.2%, respectively, p < 0.05) and the ones with submucosal/intramural myomas (36.4% vs. 15%,
respectively, p < 0.05) [16]. Despite the criticism on the strength of this study [17], it is obvious that it
provides good quality evidence on the benefits of surgical treatment of myomas.
The impact of myomectomy, in patients with submucous myomas, on IVF outcome as compared to
controls without myomas, was examined in three other studies [18e20]. The observed delivery rates
were similar in both groups. This finding indicates that submucous myomas have a negative impact on
the achievement of pregnancy, which is alleviated by myomectomy. Overall, even if the available ev-
idence is still not sufficient, previous myomectomy also does not appear to negatively affect the
chances of pregnancy in IVF cycles.
Two systematic reviews tried to examine the effect of myomectomy on the fertility potential of
woman. In 2009, Pritts et al. [7] meta-analyzing all the available studies failed to demonstrate a
beneficial effect of excision of intramural fibroids, as pregnancy and birth rates before and after surgical
excision had no statistically significant differences. Apparently, this is due to the scarcity of studies.
However, two out of 13 trials involving submucosal fibroids found a significant improvement in clinical
pregnancy rates [7].
 L.I. Zepiridis et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 34 (2016) 66e73 71

Cochrane database has also published a review on this subject. In 2012, Metwally et al. [21] collected
any prospective RCT that existed at that time, aiming to examine the consequences of myomectomy on
fertility and to compare different surgical approaches. Thus, they included only prospective random-
ized clinical trials, comparing myomectomy to no intervention at all. Unfortunately, not many suitable
papers are available in this context. Three studies fulfilled the criteria including 474 patients [21]. They
concluded that, at present, the existing RCTs, assessing the effect of myomectomy in improving fertility,
did not provide sufficient evidence. Moreover, there was no indication of significant effectiveness of
hysteroscopic myomectomy in fertility. However, they stated that these figures should be interpreted
with caution, due to the very low number of available and included studies [21]. Regarding the surgical
approach, the two available RCTs asserted that there was no difference in fertility restoration, but the
use of laparoscopy appeared to be more advantageous for postoperative recovery and morbidity
[21,22].
Based on the available evidence from all types of studies, it seems that (1) previous myomectomy
does not negatively affect pregnancy rates, thus supporting the notion that surgery per se is not
detrimental; (2) hysteroscopic excision of submucosal myomas seems to restore the fertility potential
of patients and pregnancy rates after surgery are similar to normal controls; (3) removal of intramural
myomas of size >5 cm seems to be associated with higher pregnancy rates compared to non-operated
controls, although evidence is not still sufficient; and (4) both abdominal and laparoscopic approach
are equally effective in fertility restoration, but laparoscopy is associated with better postoperative
course and less morbidity. Treatment of subserosal myomas of reasonable size is not necessary for
fertility reasons.

Current practice

Based on the currently available evidence, what would be the recommended management of fi-
broids in patients wishing pregnancy either spontaneously or after IVF?
Gynecologists should establish an integrated personalized approach considering the age, number,
size, and location of the fibroids. In the final decision for the surgical treatment of a myoma, the
following parameters should be assessed: (1) the expected impact of the lesion on patient's fertility, (2)
the effectiveness of surgical intervention, and (3) additional clinical indications associated with the
presence of the myoma.
The existing data, concerning the influence of subserosal fibroids on fertility, support the hypothesis
that they do not have any effect. Furthermore, no benefit was observed on fertility when myomectomy
was performed [3,4,6,7]. Thus, surgical removal of subserosal fibroids is not recommended for fertility
reasons. However, a decision over surgical treatment of a subserosal myoma could be justified if (1) it is
associated with symptoms due to its size or location, (2) it could create complications during preg-
nancy, taking into account its volume increase, and (3) there is another type of coexisting myoma
(Table 2).

Table 2
Current recommended practice for the treatment of myomas.

Type Indication for surgical treatment Current recommendations

Impact on reproductive Effectiveness of Additional indications

potential surgical intervention

Submucosal Significant impairment Significant improvement Abnormal Excision: Hysteroscopic

Uterine Bleeding
Intramural >4cm Significant impairment Improvement Potential pregnancy Excision: Preferably
(need further evidence) complications laparoscopic
Symptoms
Intramural <4cm Unclear Unclear Unclear Expectant managementa
Subserosal Nonsignificant Nonsignificant Potential complications Expectant managementb
a
Surgery indicated only in cases of multiple IVF failures or poor obstetrical outcome.
b
Surgery indicated only in the presence of associated symptoms or poor obstetrical outcome.
72 L.I. Zepiridis et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 34 (2016) 66e73

On the contrary, there is a general agreement that submucosal fibroids negatively affect fertility,
compared to women without fibroids. Women with submucosal myomas have reduced chances for
conception, significantly higher miscarriage rates, and reduced live birth rates, irrespective of the way
of conception [1,3,4,6,7]. Hysteroscopic removal improves fertility potential and IVF outcome [4,7].
Thus, it is reasonable to recommend surgical treatment in women wishing pregnancy. Besides, sub-
mucosal myomas are associated with abnormal uterine bleeding, which is a usual independent indi-
cation for their removal (Table 2).
Intramural fibroids have always been the gray zone and there is an ongoing debate regarding their
role in fertility and reproductive outcomes. Recent literature asserts that intramural fibroids above a
certain size (>4 cm), even without cavity distortion, may also negatively influence fertility
[4,6e8,10,11]. Furthermore, myomectomy is associated with an improvement in postsurgical concep-
tion rates, reaching that of women without fibroids, although evidence is still not sufficient [14e16].
Moreover, even if the available evidence is scanty, previous myomectomy does not appear to negatively
affect the chances of pregnancy. Therefore, myomectomy should be considered for these fibroids in
patients with infertility. It is noteworthy that intramural myomas are also associated with severe
pregnancy complications [23], which is an additional independent indication for their removal in
patients wishing pregnancy (Table 2).
Very recently, in 2015, Galliano et al. [4] in their review also conclude that the submucosal and
intramural fibroids disrupting the endometrial cavity may yield poor results after IVF attempts, a fact
that might be altered by their surgical removal. Myomectomy is recommended as the practice of choice
for fibroids ranked according to FIGO stages between 3 and 6, which are easily accessible and of
diameter 4 cm. Smaller fibroids may be removed only after multiple IVF failures and if complications
are not expected [4]. Finally, although minimally invasive surgery is preferred, there is no statistically
significant superiority when compared to the open method, regarding the achievement of a successful
term pregnancy [4].

Conclusions

The actual effect of fibroids on fertility and ART is neither completely known nor understood. The
published experience defines our best practice strategy provided that not many large, well-designed,
and properly powered studies are available. The available evidence suggests that the submucosal fi-
broids of any size and intramural uterine fibroids of size >4 cm significantly impair fertility and IVF
results. The presence of subserosal myomas has little or no effect on fertility. Myomectomy appears to
have an effect on fertility improvement in certain cases. The results of endoscopic and open myo-
mectomy are similar; thus, endoscopic treatment is the recommended approach due to its advantages
in the patient's postoperative course.

Practice points

 Submucosal fibroids negatively affect fertility when compared to women without fibroids.
 Hysteroscopic excision of submucosal fibroids improves fertility potential and in vitro
fertilization (IVF) outcome, and it is recommended for their treatment.
 Intramural fibroids of size >4 cm even without cavity distortion might negatively impair
reproductive outcome.
 Myomectomy seems to be associated with an improvement in postsurgical conception rates,
and it should be considered for intramural fibroids of size >4 cm in patients with infertility.
 Subserosal fibroids have no impact on fertility and their treatment is not recommended for
fertility reasons.
 Endoscopic treatment is the recommended approach, although it shows results similar to
those of open myomectomy, due to its advantages in patient's postoperative course
 L.I. Zepiridis et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 34 (2016) 66e73 73

Research agenda

 Effect of intramural fibroid's size and number on reproductive potential of the woman.
 Effect of the intramural fibroid's location in relation to the inner (FIGO type 4) and outer
endometrium (FIGO type 5) on fertility and pregnancy outcome.
 Effectiveness of myomectomy in restoring reproductive potential of the patients.
 Nonreproductive indications for the treatment of fibroids in fertility patients.
 Mechanisms of fibroid's action on the achievement and evolution of pregnancy.

Conflicts of interest

None.

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